1. Field of the Invention
The present invention relates to quinoline derivatives and quinazoline derivatives which have antitumor activity. More particularly, the present invention relates to quinoline derivatives and quinazoline derivatives which are therapeutically effective for diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi""s sarcoma.
2. Background Art
WO 97/17329, Japanese Patent Laid-Open No. 328782/1997, and WO 00/43366 describe quinoline derivatives and quinazoline derivatives having antitumor activity. They, however, do not disclose the compounds of the present invention.
The present inventors have found that a group of azolyl-containing quinoline derivatives and quinazoline derivatives have potent antitumor activity.
An object of the present invention is to provide compounds having potent antitumor activity.
According to the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
wherein
X and Z each independently represent CH or N;
Y represents O or S;
R1, R2, and R3, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, nitro, or amino and the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl groups are optionally substituted by a halogen atom; hydroxyl; C1-4 alkyl; C1-4 alkoxycarbonyl; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl optionally substituted by hydroxyl or C1-4 alkoxy; group R12R13Nxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 wherein R12 and R13, which may be the same or different, represent a hydrogen atom or C1-4 alkyl optionally substituted by hydroxyl or C1-4 alkoxy; or group R14xe2x80x94(S)mxe2x80x94 wherein R14 represents a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group optionally substituted by C1-4 alkyl and m is 0 or 1;
R4 represents a hydrogen atom;
R5, R6, R7, and R8, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, nitro, or amino;
R9 and R10, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, or C1-4 alkylcarbonyl and the alkyl portion of the C1-6 alkyl or C1-4 alkylcarbonyl group is optionally substituted by a halogen atom; C1-4 alkoxy; amino optionally substituted by C1-4 alkyl optionally substituted by C1-4 alkoxy; or a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group; and
R11 represents azolyl on which one or more hydrogen atoms are optionally substituted by a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl, C1-4 alkylcarbonyl, or C3-5 cyclic alkyl.
The compounds according to the present invention are therapeutically effective for diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi""s sarcoma.
Compound
The terms xe2x80x9cC1-6 alkylxe2x80x9d and xe2x80x9cC1-6 alkoxyxe2x80x9d as used herein as a group or a part of a group respectively mean straight chain or branched chain alkyl and alkoxy having 1 to 6, preferably 1 to 4 carbon atoms.
The terms xe2x80x9cC2-6 alkenylxe2x80x9d and xe2x80x9cC2-6 alkynylxe2x80x9d as used herein as a group or a part of a group respectively mean straight chain or branched chain alkenyl and alkynyl having 2 to 6, preferably 1 to 4 carbon atoms.
Examples of C1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.
Examples of C1-6 alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.
Examples of C2-6 alkenyl include allyl, butenyl, pentenyl, and hexenyl.
Examples of C2-6 alkynyl include 2-propenyl, butynyl, pentynyl, and hexynyl.
Examples of C3-5 cyclic alkyl include cyclopropyl and cyclopentyl.
The term xe2x80x9chalogen atomxe2x80x9d means a fluorine, chlorine, bromine, or iodine atom.
The saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic ring is preferably a five- to seven-membered, more preferably five- or six-membered, saturated or unsaturated carbocyclic or heterocyclic ring.
Examples of saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic rings include phenyl, cycloheptyl, cyclohexyl, and cyclopentyl.
The saturated or unsaturated three- to seven-membered heterocyclic ring contains one or more hetero-atoms selected from oxygen, nitrogen, and sulfur atoms. The term xe2x80x9chetero-atomxe2x80x9d used herein means an oxygen, nitrogen, or sulfur atom. Examples of saturated or unsaturated three- to seven-membered heterocyclic groups include pyridyl, piperidino, piperazino, morpholino, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolidinyl, and pyrazolyl.
The term xe2x80x9cazolylxe2x80x9d as used herein means a five-membered saturated or unsaturated heterocyclic group containing two or more hetro-atoms, as ring atoms, selected from the group consisting of nitrogen, sulfur, and oxygen atoms, wherein at least one of the hetero-atoms is a nitrogen atom.
R1 preferably represents a hydrogen atom.
The C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl groups, which may be represented by R1, R2, and R3, are optionally substituted by group R14xe2x80x94(S)mxe2x80x94.
The carbocyclic or heterocyclic group, which may be represented by R14, preferably represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group. The carbocyclic group more preferably represents phenyl. The heterocyclic group more preferably represents a saturated or unsaturated five-membered heterocyclic group containing one to four nitrogen atoms or a saturated or unsaturated six-membered heterocyclic group containing one or two hetero-atoms selected from nitrogen and oxygen atoms. More specifically, the hetero-atom constituting the six-membered heterocyclic group may be one nitrogen atom and one oxygen atom, or one or two nitrogen atoms.
When m is 0 (zero), xe2x80x94(S)m xe2x80x94 represents a bond.
A substituted C1-6 alkoxy group, which may be represented by R1, R2, and R3, preferably represents group R31xe2x80x94(CH2)pxe2x80x94Oxe2x80x94 wherein R31 represents a halogen atom; hydroxyl; C1-4 alkoxy; C1-4 alkoxycarbonyl; amino on which one or two hydrogen atoms each are optionally substituted by C1-4 alkyl optionally substituted by hydroxyl or C1-4 alkoxy; group R12R13Nxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 wherein R12 and R13 are as defined in formula (I); or group R14xe2x80x94(S)mxe2x80x94 wherein R14 is as defined in formula (I), and p is an integer of 1 to 6, preferably 1 to 4, more preferably 1 or 2.
R2 and R3 preferably represent C1-4 alkoxy, more preferably methoxy.
X preferably represents N or CH, and Z preferably represents CH.
Preferably, at least one of R5, R6, R7, and R8 represents a halogen atom.
Preferably, at least one of R5, R6, R7, and R8 represents a chlorine or fluorine atom.
Preferably, at least one of R5, R6, R7, and R8 represents C1-4 alkyl.
Preferably, at least one of R5, R6, R7, and R8 represents C1-4 alkoxy.
Preferably, at least one of R5, R6, R7, and R8 represents C1-4 alkylthio, trifluoromethyl, nitro, or amino.
Preferably, R5 and R6 represent a halogen atom, more preferably a chlorine or fluorine atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, nitro, or amino, and R7 and R8 represent a hydrogen atom.
R1 and R10 preferably represent a hydrogen atom.
R11 preferably represents group (i): 
wherein Q represents O, S, or NH, and R22 and R23, which may be the same or different, represent a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl.
R11 preferably represents group (ii): 
wherein Q represents O, S, or NH, and R22 and R23, which may be the same or different, represent a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl.
R11 preferably represents group (iii): 
wherein Q represents O, S, or NH, and R22 and R23, which may be the same or different, represent a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl.
R11 preferably represents group (iv): 
wherein Q represents O, S, or NH, and R22 represents a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl.
In groups (i) and (ii), R23 preferably represents a hydrogen atom.
R11 preferably represents optionally substituted azolyl selected from the group consisting of imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl.
A preferred group of compounds represented by formula (I) include compounds represented by formula (Ia): 
wherein
X represents CH or N,
R15 and R16, which may be the same or different, represent C1-6 alkoxy,
R17, R18, R19, and R20, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, nitro, or amino,
R21 represents azolyl on which one or more hydrogen atoms are optionally substituted by a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl.
R15 and R16 preferably represent methoxy.
Preferably, at least one of R17, R18, R19, and R20 represents a halogen atom.
Preferably, at least one of R17, R18, R19, and R20 represents a chlorine or fluorine atom.
Preferably, at least one of R17, R18, R19, and R20 represents C1-4 alkyl.
Preferably, at least one of R17, R18, R19, and R20 represents C1-4 alkoxy.
Preferably, at least one of R17, R18, R19, and R20 represents C1-4 alkylthio, trifluoromethyl, nitro, or amino.
Preferably, R17 and R18 represent a halogen atom, more preferably a chlorine or fluorine atom, C1-4alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, nitro, or amino, and R19 and R20 represent a hydrogen atom.
R21 preferably represents group (i), (ii), (iii), or (iv).
R21 preferably represents optionally substituted azolyl selected from the group consisting of imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl.
A group of more preferred compounds represented by formula (I) include compounds represented by formula (Ib): 
wherein MeO represents methoxy; X represents CH or N; R17, R18, and R19, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, nitro, or amino; and R21 represents group (i),(ii),(iii), or (iv).
In formula (Ib), preferably, R21 represents group (i) wherein Q represents O, more preferably, both R22 and R23 represent a hydrogen atom, or one of R22 and R23 represents a hydrogen atom and the other represents C1-4 alkyl.
In formula (Ib), preferably, R21 represents group (iii) wherein Q represents S, more preferably, both R22 and R23 represent a hydrogen atom, or one of R22 and R23 represents a hydrogen atom and the other represents C1-4 alkyl.
Specific examples of the compounds according to the present invention include compounds prepared in Examples 1 to 75.
More preferred compounds according to the present invention include the following compounds. Numerical values in parentheses indicate Example No.
(4) N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-Nxe2x80x2-(5-methyl-3-isoxazolyl)urea;
(27) N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluoro-phenyl}-Nxe2x80x2-(1,3-thiazol-2-yl)urea;
(28) N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluoro-phenyl}-Nxe2x80x2-(4-methyl-1,3-thiazol-2-yl)urea; and
(38) N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)-oxy]phenyl}-Nxe2x80x2-(1,3-thiazol-2-yl)urea.
The compounds according to the present invention may form pharmaceutically acceptable salts thereof. Preferred examples of such salts include: alkali metal or alkaline earth metal salts such as sodium salts, potassium salts or calcium salts; hydrohalogenic acid salts such as hydrofluoride salts, hydrochloride salts, hydrobromide salts, or hydroiodide salts; inorganic acid salts such as nitric acid salts, perchloric acid salts, sulfuric acid salts, or phosphoric acid salts; lower alkylsulfonic acid salts such as methanesulfonic acid salts, trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts; arylsulfonic acid salts such as benzenesulfonic acid salts or p-toluenesulfonic acid salts; organic acid salts such as fumaric acid salts, succinic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, maleic acid salts, acetic acid salts, malic acid salts, lactic acid salts, or ascorbic acid salts; and amino acid salts such as glycine salts, phenylalanine salts, glutamic acid salts, or aspartic acid salts.
Compounds of the present invention can be produced, for example, according to scheme 1 and scheme 2. 
wherein Rxe2x80x2 represents C1-6 alkyl or the like, and R1, R2, R3, R4, R5, R6, R7, R8, and X are as defined in formula (I).
Starting compounds necessary for the synthesis of the compounds according to the present invention are commercially available or may be easily produced by a conventional method. For example, a 4-chloroquinoline derivative can be synthesized by a conventional method as described, for example, in Org. Synth. Col. Vol. 3, 272 (1955), Acta Chim. Hung., 112, 241 (1983), or WO 98/47873.
Alternatively, the 4-chloroquinazoline derivative may be produced by first (1) reacting a benzoic ester with formamide to give a quinazolone derivative and then (2) heating the 4-quinazolone derivative in the presence of phosphorus oxychloride using toluene or sulfolane as a solvent. The quinazolone derivative is generally synthesized in the presence of a solvent such as a benzoic ester, sodium methoxide, formamide, N,N-dimethyl formamide, or methanol.
Next, a 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative can be produced by reacting nitrophenol with the 4-chloroquinoline derivative or corresponding quinazoline derivative in the presence or absence of a suitable solvent to synthesize a 4-(nitrophenoxy)quinoline derivative or a corresponding quinazoline derivative and then stirring the 4-(nitrophenoxy)quinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, N,N-dimethyl formamide, in the presence of a catalyst, for example, palladium hydroxide-carbon, palladium-carbon, under a hydrogen atmosphere. Alternatively, a 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative may be produced by reacting aminophenol with the 4-chloroquinoline derivative or corresponding quinazoline derivative in the presence of a base, for example, sodium hydride.
Alternatively, a 4-(aminophenoxy)quinazoline derivative may be produced by dissolving aminophenol in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in an organic solvent in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium bromide, or in the absence of the catalyst. 
wherein Hal represents a halogen atom, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and X are as defined in formula (I).
A substituent can be inserted into R9 by reacting the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative thus obtained with an acid chloride or an acid anhydride in the presence of a base and then reducing the reaction product with aluminum lithium hydride or the like (step 1A).
Alternatively, a substituent can be inserted into R9 by reacting the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative with an aldehyde or a ketone to give an imine compound and then reacting the imine compound with sodium boron cyanohydride or the like (step 1B).
The compound represented by formula (I) can be produced by reacting the derivative having a substituent at R9 with an isocyanate derivative according to a conventional method (step 2) and reacting the reaction product with a suitable alkylating agent (R10Hal) in the presence of a base, for example, sodium hydride (step 3).
R9 and R10 may also be introduced by reacting a urea derivative, wherein R9 and/or R10 represent a hydrogen atom, with a suitable alkylating agent (R10Hal) in the presence of a base, for example, sodium hydride, like step 3 (steps 5 and 7).
The urea derivative, wherein R9 and/or R10 represent a hydrogen atom, can be produced by reacting the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative prepared in scheme 1 with an isocyanate derivative according to a conventional method, or by adding triphosgene to the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative in the presence of a base, for example, triethylamine, and then reacting the mixture with a suitable amine derivative (R11NH2 or R10R11NH) (steps 4 and 6).
The compound represented by formula (I), wherein Y represents S, can be produced by reacting an aminothiophenol derivative with a 4-chloroquinoline derivative or a corresponding quinazoline derivative in a suitable solvent, for example, chlorobenzene according to scheme 1 to give a 4-(quinolylsulfanyl)aniline derivative or a 4-(quinazolinylsulfanyl)aniline derivative and then forming a urea portion according to scheme 2.
Use of Compounds/pharmaceutical Compositions
The compounds according to the present invention have inhibitory activity to tumor proliferation in vivo (Pharmacological Test Examples 2, 3, and 4).
Further, the compounds according to the present invention inhibit in vitro the autophosphorylation in a human KDR intracellular region caused by the stimulation of NIH3T3 cells, which stably develop human KDR, with VEGF (vascular endothelial growth factor) (Pharmacological Test Example 1). Binding of VEGF to KDR, a receptor for VEGF on a cell membrane, induces the activation of MAPK (mitogen-activated protein kinase) or the like through the autophosphorylation of the KDR intracellular region with tyrosine kinase (Shibuya M, Ito N, Claesson-Welsh L., in Curr. Topics Microbiol Immunol., 237, 59-83 (1999); and Abedi, H. and Zachary, I., J. Biol. Chem., 272, 15442-15451 (1997)). The activation of MAPK is known to play an important role in the growth of vascular endothelial cells in angiogenesis (Merenmies, J. et al., Cell Growth and Differ., 83-10 (1997); and Ferrara, N. and Davis-Smyth, T., Endocr. Rev., 18, 4-25 (1997)). Therefore, the compounds according to the present invention have angiogenesis inhibitory activity.
Angiogenesis at pathologic sites is known to be deeply involved in diseases, such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi""s sarcoma, and metastasis of solid tumors (Folkman, J. Nature Med. 1: 27-31 (1995); Bicknell, R., Harris, A. L. Curr. Opin. Oncol. 8: 60-65 (1996)). Therefore, the compounds according to the present invention can be used in the treatment of these diseases.
According to the present invention, there is provided a pharmaceutical composition comprising the compound according to the present invention. The pharmaceutical composition according to the present invention may be used in the treatment of diseases, such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi""s sarcoma, and metastasis of solid tumors.
The compounds according to the present invention can be administered to human and non-human animals orally or parenterally by administration routes, for example, intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, or percutaneous administration. Therefore, the pharmaceutical composition comprising as an active ingredient the compound according to the present invention is formulated into suitable dosage forms according to the administration routes.
Specifically, oral preparations include tablets, capsules, powders, granules, and syrups, and parental preparations include injections, suppositories, tapes, and ointments.
These various preparations may be prepared by conventional methods, for example, with commonly used pharmaceutically acceptable carriers, such as excipients, disintegrants, binders, lubricants, colorants, and diluents.
Excipients include, for example, lactose, glucose, corn starch, sorbit, and crystalline cellulose; disintegrants include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, and dextrin; binders include, for example, dimethylcellulose, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, and polyvinyl pyrrolidone; lubricants include, for example, talc, magnesium stearate, polyethylene glycol, and hydrogenated vegetable oils.
In preparing the injections, if necessary, for example, buffers, pH adjustors, stabilizers, tonicity agents, and preservatives may be added.
The content of the compound according to the present invention in the pharmaceutical composition according to the present invention may vary depending on the dosage form. In general, however, the content is 0.5 to 50% by weight, preferably 1 to 20% by weight, based on the whole composition.
The dose may be appropriately determined in consideration of, for example, the age, weight, sex, difference in diseases, and severity of the condition of individual patients, and the preparation may be administered, for example, in an amount of 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg. This dose is administered once a day or divided doses of several times daily.
The compound according to the present invention may be administered in combination with other medicament(s). In this case, the compound according to the present invention may be administered simultaneously with or after or before the administration of other medicament(s). For example, when the subject disease is malignant tumor, the compound according to the present invention can act on target vascular endothelial cells to allow the tumor to regress, followed by the administration of an anti-cancer agent to effectively eliminate the tumor. The type, administration intervals and the like of the anti-cancer agent may be determined depending upon, for example, the type of cancer and the condition of patients. This treatment method can apply to diseases other than the malignant tumor.
According to the present invention, there is provided use of the compound according to the present invention, for the manufacture of a medicament for a disease selected from the group consisting of tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi""s sarcoma.
Further, according to the present invention, there is provided a method for treating a disease selected from the group consisting of tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi""s sarcoma, comprising the step of administering a therapeutically effective amount of the compound according to the present invention, optionally together with a pharmaceutically acceptable carrier, to a mammal, for example, a human.
Furthermore, according to the present invention, there is provided a method for inhibiting the angiogenesis of target blood vessels, comprising the step of bringing the compound according to the present invention into contact with vascular endothelial cells of target blood vessels. Target blood vessels include blood vessels involved in feedings to tissues causative of diseases, for example, tumor tissues, retinopathy tissues, or rheumatism tissues. The compound according to the present invention may be brought into contact with the vascular endothelial cells, for example, by general administration, for example, intravenous administration or oral administration; local administration, for example, percutaneous administration or intraarticular administration; or drug targeting using a carrier, for example, liposome, lipid microsphere, or polymeric forms of drugs.